Yan Yu

Shanghai Jiao Tong University, Shanghai, Shanghai Shi, China

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Publications (38)104.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect of many chemoagents, resulting in weight loss, diarrhea, and even death. The current treatments for CIM are palliative and have limited benefit. Interleukin-1 receptor antagonist is a natural antagonist of interleukin-1. Our previous studies showed the protective effect of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on the intestine in mice after 5-fluorouracil chemotherapy. In this study, we further evaluated rhIL-1Ra in the treatment of CIM induced by different chemoagents and their combination. Normal as well as tumor-bearing mice were administered oxaliplatin (L-OHP), 5-fluorouracil, or their combination to induce intestinal mucositis and mortality. rhIL-1Ra administered after the chemotherapy, but not after the onset of diarrhea, significantly improved mouse survival, attenuated body weight loss, and reduced the incidence, severity, and duration of diarrhea. Histological examination showed that rhIL-1Ra-treated mice had a relatively intact mucosa structure, more proliferating crypt cells, and higher acid mucin content than the vehicle-treated mice. rhIL-1Ra suppressed crypt apoptosis by reducing the levels of proapoptotic proteins in wild-type, but not in IL-1RI or p53 mice. In addition, rhIL-1Ra was as effective as octreotide acetate in the treatment of chemotherapy-induced diarrhea, but with the advantage of reducing the epithelial apoptosis, the major cause of CIM. Importantly, the tumor sensitivity to chemotherapy was not affected by rhIL-1Ra. Thus, our data strongly suggest that rhIL-1Ra may be useful for the treatment of intestinal mucositis and improving the quality of life for cancer patients on chemotherapy.
    Anti-cancer drugs. 07/2014;
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    ABSTRACT: Chemotherapy-induced mucositis (CIM) is a major does limiting side-effect of chemoagents such as 5-fluorouracil (5-FU). Molecules involved in this disease process are still not fully understood. We proposed that the homeostatically regulated genes during CIM may participate in the disease. A cluster of such genes were previously identified by expression gene-array from the mouse jejunum in 5-FU-induced mucositis model. Here, we report that CXCL4 is such a homeostatically regulated gene and serves as a new target for the antibody treatment of CIM. CXCL4 and its receptor CXCR3 were confirmed at both the gene and protein levels to be homeostatically regulated during 5-FU-induced mucositis. Using of CXCL4 neutralizing monoclonal antibody (CXCL4mab) decreased the incidence, severity, and duration of the chemotherapy-induced diarrhea, the major symptom of CIM, in a 5-FU mouse CIM model. Mechanistically, CXCL4mab reduced the apoptosis of the crypt epithelia by suppression of the 5-FU-induced expression of p53 and Bax through its receptor CXCR3. The downstream signaling pathway of CXCL4 in activation of the epithelial apoptosis was identified in an intestinal epithelial cell line (IEC-6). CXCL4 activated the phosphorylation of p38 MAPK, which mediated the stimulated expression of p53 and Bax, and resulted in the ultimate activation of Caspase-8, -9, and -3. Taken together, activation of CXCL4 expression by 5-FU in mice participates in 5-FU-induced intestinal mucositis through upregulation of p53 via activation of p38-MAPK, and CXCL4mab is potentially beneficial in preventing CIM in the intestinal tract.
    Cancer biology & therapy 05/2014; 15(8). · 3.29 Impact Factor
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    ABSTRACT: Chemotherapy-induced intestinal mucositis (CIM) is a major dose-limiting side effect, resulting from the nonspecific cytoablative actions of chemoagents, including 5-fluorouracil (5-FU) and irinotecan (CPT-11). Preventive strategies are urgently needed for the predictable CIM. Previously, we have demonstrated an important role of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) in the prevention of cyclophosphamide-induced mucositis in mice. In this study, the preventive role of rhIL-1Ra was further evaluated in 5-FU- and CPT-11-induced mucositis mouse models. rhIL-1Ra pretreatment reduced the incidence, severity, and duration of chemotherapy-induced diarrhea, through attenuating crypt apoptosis and improving crypt survival in wild-type mice, but not in IL-1RI(-/-), p53(-/-), and p21(-/-) mice. Further studies demonstrated that rhIL-1Ra promoted the cell cycle arrest of intestinal crypt epithelia (ICE) through elevating the cellular level of p21(WAF1) and p27(KIP1), which was abolished in IL-1RI(-/-) and p53(-/-) mice, and in p21(WAF1) and p27(KIP1) silenced IEC-6 cells. Importantly, the tumor growth and sensitivity to chemotherapy were not affected by rhIL-1Ra in cultures of tumor cell lines and in a syngeneic tumor-transplantation mouse model. The present study demonstrated that rhIL-1Ra effectively and specifically protected ICE from chemotoxicity through reversible reduction of the basal level of IL-1 signaling to promote normal cell cycle arrest, but not tumor cells. Our findings support the clinical development of rhIL-1Ra in the prevention of CIM.
    Pharmacological Research 03/2014; · 4.35 Impact Factor
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    ABSTRACT: Midkine (MK) and pleiotrophin (PTN) belong to the subfamily of heparin binding growth factors. They have ca. 50% structural homology, with similar C- and N-domains as well as comparable binding affinity to heparin, glycoproteins and proteoglycans. Both MK and PTN have diverse functions, such as mitogenicity, inflammation, angiogenesis, oncogenesis and stem cell self-renewal. The high expression of MK and PTN in many kinds of cancers makes them excellent as cancer biomarkers and targets for anticancer drug development. In addition, the important roles of MK and PTN in the regeneration of tissues, such as myocardium, cartilage, neuron, muscle, and bone, make them attractive candidates for the treatment of degenerative diseases such as myocardiac and cerebral infarction, Alzheimer's disease, Parkinson's disease and skeletal muscle injury. As a result, there has been a growing interest in the mechanisms of MK and PTN function, including the diverse receptors on the cell membrane and complex signal pathways in the cytoplasm. This work reviews the structures of MK and PTN, as well as the receptors and the intracellular signal pathways involving MK and PTN which will pave the way for future development of MK and PTN therapeutics.
    Biological & Pharmaceutical Bulletin 01/2014; 37(4):511-20. · 1.85 Impact Factor
  • Pharmacological Research. 01/2014;
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    ABSTRACT: Recent developments in nanotechnology have led to significant advancements in point-of-care (POC) nucleic acid detection. The ability to sense DNA and RNA in a portable format leads to important applications for a range of settings, from on-site detection in the field to bedside diagnostics, in both developing and developed countries. We review recent innovations in three key process components for nucleic acid detection: sample preparation, target amplification, and read-out modalities. We discuss how the advancements realized by nanotechnology are making POC nucleic acid detection increasingly applicable for decentralized and accessible testing, in particular for the developing world.
    Nanoscale 09/2013; · 6.73 Impact Factor
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    ABSTRACT: Chemokines have been shown to play an important role in the pathogenesis of pancreatitis, but the role of chemokine CXCL9 in pancreatitis is poorly understood. The aim of this study was to investigate whether CXCL9 was a modulating factor in chronic pancreatitis. Chronic pancreatitis was induced in Sprague-Dawley rats by intraductal infusion of trinitrobenzene sulfonic acid (TNBS) and CXCL9 expression was assessed by immunohistochemistry, Western blot analysis and enzyme linked immunosorbent assay (ELISA). Recombinant human CXCL9 protein (rCXCL9), neutralizing antibody and normal saline (NS) were administered to rats with chronic pancreatitis by subcutaneous injection. The severity of fibrosis was determined by measuring hydroxyproline in pancreatic tissues and histological grading. The effect of rCXCL9 on activated pancreatic stellate cells (PSCs) in vitro was examined and collagen 1α1, TGF-β1 and CXCR3 expression was assessed by Western blot analysis in isolated rat PSCs. Chronic pancreatic injury in rats was induced after TNBS treatment and CXCL9 protein was markedly upregulated during TNBS-induced chronic pancreatitis. Although parenchymal injury in the pancreas was not obviously affected after rCXCL9 and neutralizing antibody administration, rCXCL9 could attenuate fibrogenesis in TNBS-induced chronic pancreatitis in vivo and exerted antifibrotic effects in vitro, suppressing collagen production in activated PSCs. In conclusion, CXCL9 is involved in the modulation of pancreatic fibrogenesis in TNBS-induced chronic pancreatitis in rats, and may be a therapeutic target in pancreatic fibrosis.
    Cytokine 06/2013; · 2.52 Impact Factor
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    ABSTRACT: Cyclophosphamide (CY), targeting to fast dividing cells, results in bone marrow (BM) suppression, which is the most common side effect of cancer chemotherapy. Interleukin-1 receptor antagonist (IL-1Ra), activated by variety of chemotherapeutic drugs, is a natural inhibitor of interleukin-1 (IL-1) and blocks the functional IL-1 receptor signaling. Our previous studies showed the protective effect of recombinant murine IL-1Ra on hematopoiesis in mice after treatment with chemotherapeutic agent 5-fluorouracil. In this report, we demonstrate that the pretreatment use of recombinant human IL-1Ra (rhIL-1Ra) significantly alleviated chemotherapy-induced peripheral blood injury in mice, and reduced the incidence and severity of neutropenia in beagle dogs. Moreover, acute lethal toxicity in single and repeated CY treatment was markedly reduced by rhIL-1Ra administration. The chemoprotective role of rhIL-1Ra is attributed to the attenuated BM damage, accelerated recovery of BM cells, and enhanced survival of hematopoietic progenitor cells which expressed high level of aldehyde dehydrogenase and IL-1 receptor type I. Thus, our data strongly suggest that the prophylactic use of exogenous rhIL-1Ra renders BM primitive hematopoietic cells resistant to chemotherapy, which provides novel strategies to prevent BM suppression in clinical settings.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 03/2013; 67(2):108-15. · 2.24 Impact Factor
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    ABSTRACT: Transforming growth factor-β (TGF-β) superfamily controls many physiological processes such as cell proliferation and differentiation, immune responses, wound repair and various endocrine activities. As a member of TGF-β, activin A can maintain the pluripotency of embryonic stem cells. We report here that activin A exhibited cell type-dependent function of expanding the human primitive hematopoietic cells isolated from umbilical cord blood (UCB). However, the multipotency of the cells pretreated with activin A was exhausted in the sequential dilution culture. In conclusion, activin A may not be a key factor, but a regulator, in the multipotency maintenance of primitive hematopoietic cells and the application of activin A in the hematopoietic stem/progenitor cells (HS/PCs) culture expansion remains a significant challenge.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 09/2012; · 2.24 Impact Factor
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    ABSTRACT: S100 proteins belong to a family of small, acidic, EF-hand Ca ( 2+) -binding proteins and have been found to exert both intracellular and extracellular functions in regulation of Ca ( 2+) homeostasis, cytoskeletal dynamics, cell cycle, motility and differentiation. As a result, they have been widely investigated for their association with diseases, such as, neurological diseases, cardiomyopathy, neoplasias and inflammatory diseases. To facilitate further studies of S100 proteins, we reported a simple and efficient method for the expression and purification of human S100A4 and S100A11 proteins in Escherichia coli. Since S100 proteins share many common physical and chemical characteristics, we expect that this approach can be extended to the production of most S100 proteins.
    Bioengineered. 09/2012; 4(1).
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    ABSTRACT: Alterations in gene expression after chemotherapy may potentially help to identify mediators that induce suppression or regeneration in bone marrow. This paper reports our observation that the expression of the chemokine monokine induced by IFN-γ (Mig) and its receptor CXCR3 was significantly activated in mice after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The neutralization of antibodies against the activated Mig increased the survival rate and accelerated BM recovery after chemotherapy. In addition, elevation of Mig plasma levels after 5-FU treatment corresponded with increased mortality. The cell cycle-inhibiting effect of the prophylactic administration of Mig protected hematopoietic progenitor cells (HPCs) from 1-β-d-arabinofuranosylcytosine in spleen colony assays and enhanced the irradiated recipients' survival. In CXCR3(-/-) mice, Mig did not propagate BM suppression, indicating that the suppressive effect of Mig is dependent on CXCR3. On the one hand, Mig stimulated p70 S6K and Erk1/2 pathways in mesenchymal stroma cells, inhibiting mesenchymal stroma cell-dependent HPC expansion. Moreover, Mig suppressed the STAT5 pathway in HPCs, inhibiting leukocyte differentiation. Our results strongly suggest that Mig contributes to the acute lethal toxicity arising from 5-FU administration. Neutralization of Mig may offer new strategies to alleviate BM toxicity with potentially dramatic implications for chemotherapy.
    Blood 04/2012; 119(21):4868-77. · 9.78 Impact Factor
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    ABSTRACT: S100A6, as a member of S100 protein family, have biological functions in cell proliferation, differentiation, morphology, cytoskeletal organization and apoptosis. In the last three decades, S100A6 has been caught more and more attention. Here, we introduced a simple and efficient method for producing high-purity recombinant human S100A6 from Escherichia coli culture with low level of endotoxin. We further demonstrated its biological activities for triggering SH-SY5Y cells apoptosis in vitro. These results can facilitate the study of physiological and pathological roles of S100A6 and other members of S100 family proteins.
    Protein Expression and Purification 03/2012; 83(1):98-103. · 1.43 Impact Factor
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    ABSTRACT: Monokine induced by IFN-γ (Mig) is a member of CXC-chemokines and recruits T-lymphocytes to activate the immune response. In recent years, it has raised much interest in the areas of autoimmune disease and allograft rejection, as the production of recombinant human Mig (rHuMig) would be of considerable significance for both research and potential clinical use. Here we report the expression, preparation and characterization of non-tagged recombinant human Mig (rHuMig) using a prokaryotic expression system. Following expression in Escherichia coli (E. coli) BL21, the 103 amino acid residue of rHuMig was purified from bacteria inclusion bodies with a one-step S-Sepharose cation exchange chromatography. The product was immunologically characterized via Western blot and its purity was determined via SDS-PAGE and silver staining to be above 99%, with an endotoxin level <0.5EU/μg via a chemotaxis assay, rHuMig demonstrated chemotactic activity on mouse spleen lymphocytes with an ED50 of 15 ng/mL. Additionally, using a proliferation assay, rHuMig significantly inhibited proliferation of the human bladder cell line T24. In vivo experiments revealed that rHuMig could inhibit mouse bone marrow mononuclear cells cycling into the S-phase and reduced intestinal cell proliferation. Our results demonstrate that rHuMig is fully functional in the mouse model.
    Protein Expression and Purification 03/2012; 82(1):205-11. · 1.43 Impact Factor
  • Source
    Di Xiang, Yan Yu, Wei Han
    01/2012; , ISBN: 978-953-307-831-1
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    ABSTRACT: Chronic pancreatitis is a progressive inflammatory disease featuring irreversible irregular scarring of the exocrine parenchyma characterized by acinar destruction and fibrosis subsequent to inflammation in the pancreas. Despite decades of research, the knowledge is limited to the treatment of this disease. After finding a connection between interleukin-1β (IL-1β) and interleukin-1 receptor antagonist (IL-1Ra) in caerulein-induced chronic pancreatitis, we assumed that recombinant human IL-1Ra (rhIL-1Ra), the natural antagonist of IL-1β, might have a protective role in chronic pancreatitis in mice. Chronic pancreatitis was induced by repetitive intraperitoneal injections of caerulein in C57/BL mice followed by a consecutive administration of rhIL-1Ra (10mg/kg). Collagen content and histological changes in the pancreas as well as serum amylase and lipase were measured. We found that rhIL-1Ra significantly decreased the hydroxyproline and the fibrotic area in the pancreas after the caerulein challenge. Caerulein-induced serum amylase elevation and tissue damage were also attenuated in rhIL-1Ra treated mice. Our results reveal a potential role of rhIL-1Ra in protecting mice against caerulein-induced chronic pancreatitis and lead to a conclusion that this protein may be a potential candidate agent for the treatment of chronic pancreatitis in humans.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 01/2012; 66(2):83-8. · 2.24 Impact Factor
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    ABSTRACT: Using mouse gene expression microarray analysis, we earlier obtained dynamic profiles of whole genome expression in the CCl(4)-induced liver injury mouse model. CXCL14 expression was increased in the liver injury phase and returned to normal after liver regeneration suggesting its involvement in the liver injury or regeneration regulation. The role of CXCL14 in liver injury was investigated. The dynamic of CXCL14 transcription was analyzed in CCl(4)-induced mouse liver damage by qRT-PCR. Plasmid mediated CXCL14 overexpression and antibody neutralization of endogenous CXCL14 were used to demonstrate its effects and mechanisms on CCl(4)-induced liver injury and acute liver failure. We showed that CXCL14 expression was immediately upregulated post CCl(4) injection with a dose-dependent response. CXCL14 over-expression aggravated CCl(4)-induced liver injuries, evidenced by enhanced acidophilic change and necrosis of hepatocyte, increased fat deposition in hepatocytes (P<0.01), and inhibited hepatocyte proliferation (P<0.01). On the contrary, anti-CXCL14 antibody treatment reduced the severity of CCL4-induced liver injuries Significant reductions in hepatic necrosis area (P<0.05), the liver fat deposition (P<0.01), and the lipid peroxidation measured by serum MDA (P<0.05) were observed. Importantly, the antibody treatment reduced the mouse mortality caused by CCl4-induced liver failure (P<0.05). The data suggest that CXCL14 and its receptor present potential targets for the treatment of liver diseases.
    European journal of pharmacology 12/2011; 671(1-3):120-7. · 2.59 Impact Factor
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    ABSTRACT: Autologous chondrocyte implantation (ACI) is widely used for the repair of cartilage defects. However, due to the lack of chondrocyte growth factor and dedifferentiation of the cultured primary chondrocytes, cell source has limited the clinical potential of ACI. Auricular cartilage is an attractive potential source of cells for cartilage tissue engineering. Here we demonstrated that recombinant human midkine (rhMK) significantly promoted proliferation of rat primary auricular chondrocytes cultured and passaged in monolayer, which was mediated by the activation of mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Furthermore, rhMK attenuated the dedifferentiation of cultured chondrocytes by maintaining the expression of chondrocyte-specific matrix proteins during culture expansion and passage. Importantly, rhMK-expanded chondrocytes reserved their full chondrogenic potential and redifferentiated into elastic chondrocytes after being cultured in high density. The results suggest that rhMK may be used for the preparation of chondrocytes in cartilage tissue engineering.
    Experimental Biology and Medicine 09/2011; 236(11):1254-62. · 2.80 Impact Factor
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    ABSTRACT: Chemotherapy induced intestinal mucositis is still an unmet medical problem. 5-fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra has less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy induced intestinal mucositis are warranted.
    Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 06/2011; 65(5):339-44. · 2.24 Impact Factor
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    ABSTRACT: Cyclophosphamide is a cytotoxic chemotherapy drug that causes severe damages to hematopoietic and gastrointestinal systems. The aim of this study is to evaluate the protective effects of recombinant human interleukin-1 receptor antagonist (rhIL-1Ra) on chemotherapy-induced mucositis (CIM) in a murine model of cyclophosphamide chemotherapy. In single chemotherapy models, equal numbers of gender-matched Balb/c mice were administered intraperitoneal injections of rhIL-1Ra at a dose of 1 mg/kg/day or vehicle for 5 continuous days, followed by single intraperitoneal injection of cyclophosphamide at doses of 100, 300, 400 or 550 mg/kg. In multiple cycles of chemotherapy models, mice were administered rhIL-1Ra or vehicle for 5 days, followed by cyclophosphamide injection at a dose of 300 mg/kg. The course has been repeated for 2 or 3 times with a 1-month break in between. In continuous chemotherapy models, mice were administered rhIL-1Ra or vehicle for 5 days, followed by cyclophosphamide injections at doses of 150 or 200 mg/kg/day for 3 days. Body weight and diarrhea were observed in each model. Intestinal morphology was observed in mice received 300 or 400 mg/kg cyclophosphamide chemotherapy. CIM was induced by cyclophosphamide in a dose-dependent manner. RhIL-1Ra attenuated CIM with reduced body weight loss, diarrhea, intestinal injuries and mortality after CY chemotherapy. The pretreatment with rhIL-1Ra effectively protected murine gastrointestinal system from clinically relevant cyclophosphamide regimens. The identification of these protective effects of rhIL-1Ra highlights clinical values of this protein for the prevention of CIM.
    Cancer Chemotherapy and Pharmacology 06/2011; 67(6):1445-53. · 2.80 Impact Factor
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    ABSTRACT: Mouse CXCL14/BRAK is a monocyte-selective chemokine which is expressed in almost all normal tissues. A flood of reports on its new functions of tumor suppression and fat metabolism modulation has left CXCL14 a potential therapeutic candidate for these diseases. Therefore, a simple accessible method is on demand for large-scale production of recombinant mouse CXCL14 protein for in vivo animal studies. Here, we introduce an efficient method for large-scale production of recombinant mouse CXCL14, by which an 18-mg protein is produced from 2-L Escherichia coli culture with good bioactivity and low level of endotoxin.
    Applied biochemistry and biotechnology 03/2011; 164(8):1366-75. · 1.94 Impact Factor

Publication Stats

155 Citations
104.34 Total Impact Points


  • 2008–2014
    • Shanghai Jiao Tong University
      • • School of Agriculture and Biology
      • • School of Pharmacy
      Shanghai, Shanghai Shi, China
  • 2012
    • Shanghai University
      Shanghai, Shanghai Shi, China
    • Renji Hospital
      Shanghai, Shanghai Shi, China
  • 2010
    • Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
      Shanghai, Shanghai Shi, China
    • Tongji Medical University
      • Department of Gastroenterology
      Shanghai, Shanghai Shi, China